HDAC inhibition induces EMT and alterations in cellular iron homeostasis to augment ferroptosis sensitivity in SW13 cells.
Oliveira Thais,Hermann Evan,Lin Daniel,Chowanadisai Winyoo,Hull Elizabeth,Montgomery McKale
Epithelial-to-mesenchymal transition (EMT) is an essential mechanism for development and wound healing, but in cancer it also mediates the progression and spread of aggressive tumors while increasing therapeutic resistance. Adoption of a mesenchymal state is also associated with increased iron uptake, but the relationship between EMT and the key regulators of cellular iron metabolism remains undefined. In this regard, the human adrenal cortical carcinoma SW13 cell line represents an invaluable research model as HDAC inhibitor treatment can convert them from an epithelial-like (SW13-) cell type to a mesenchymal-like (SW13+) subtype. In this study we establish SW13 cells as a model for exploring the link between iron and EMT. Increased iron accumulation following HDAC inhibitor mediated EMT is associated with decreased expression of the iron export protein ferroportin, enhanced ROS production, and reduced expression of antioxidant response genes. As availability of redox active iron and loss of lipid peroxide repair capacity are hallmarks of ferroptosis, a form of iron-mediated cell death, we next examined whether HDAC inhibitor treatment could augment ferroptosis sensitivity. Indeed, HDAC inhibitor treatment synergistically increased cell death following induction of ferroptosis. The exact mechanisms by which HDAC inhibition facilitates cell death following ferroptosis induction requires further study. As several HDAC inhibitors are already in use clinically for the treatment of certain cancer types, the findings from these studies have immediate implications for improving iron-targeted chemotherapeutic strategies.
Targeting Ferroptosis for Lung Diseases: Exploring Novel Strategies in Ferroptosis-Associated Mechanisms.
Ma Tian-Liang,Zhou Yong,Wang Ci,Wang Lu,Chen Jing-Xian,Yang Hui-Hui,Zhang Chen-Yu,Zhou Yong,Guan Cha-Xiang
Oxidative medicine and cellular longevity
Ferroptosis is an iron-dependent regulated necrosis characterized by the peroxidation damage of lipid molecular containing unsaturated fatty acid long chain on the cell membrane or organelle membrane after cellular deactivation restitution system, resulting in the cell membrane rupture. Ferroptosis is biochemically and morphologically distinct and disparate from other forms of regulated cell death. Recently, mounting studies have investigated the mechanism of ferroptosis, and numerous proteins play vital roles in regulating ferroptosis. With detailed studies, emerging evidence indicates that ferroptosis is found in multiple lung diseases, demonstrating that ferroptosis appears to be particularly important for lung diseases. The mounting interest in ferroptosis drugs specifically targeting the ferroptosis mechanism holds substantial therapeutic promise in lung diseases. The present review emphatically summarizes the functions and integrated molecular mechanisms of ferroptosis in various lung diseases, proposing that multiangle regulation of ferroptosis might be a promising strategy for the clinical treatment of lung diseases.
Ruxolitinib exerts neuroprotection via repressing ferroptosis in a mouse model of traumatic brain injury.
Chen Xueshi,Gao Cheng,Yan Ya'nan,Cheng Zhiqi,Chen Guang,Rui Tongyu,Luo Chengliang,Gao Yuan,Wang Tao,Chen Xiping,Tao Luyang
Traumatic brain injury (TBI) is a major cause of death and disability worldwide. Various forms of cells death are involved in the pathological process of TBI, without exception to ferroptosis, which is mainly triggered by iron-dependent lipid peroxidation. Although there have been studies on ferroptosis and TBI, the effect of ruxolitinib (Ruxo), one type of FDA approved drugs for treating myelofibrosis, on the process of ferroptosis post-TBI is remained non-elucidated. Therefore, using a controlled cortical impact device to establish the mouse TBI model, we examined the effect of Ruxo on TBI-induced ferroptosis, in which the inhibitor of ferroptosis, Ferrostatin-1 (Fer-1) was used as a positive control. Moreover, we also respectively explored the effects of these two interventions on neurological deficits caused by TBI. We firstly examined the expression patterns of ferroptosis-related markers at protein level at different time points after TBI. And based on the expression changes of these markers, we chose 12 h post-TBI to prove the effect of Ruxo on ferroptosis. Importantly, we found the intensely inhibitory effect of Ruxo on ferroptosis, which is in parallel with the results obtained after Fer-1-treatment. In addition, these two treatments both alleviated the content of brain water and degree of neurodegeneration in the acute phase of TBI. Finally, we further confirmed the neuroprotective effect of Ruxo or Fer-1 via the wire-grip test, Morris water maze and open field test, respectively. Thereafter, the lesion volume and iron deposition were also measured to certificate their effects on the long-term outcomes of TBI. Our results ultimately demonstrate that inhibiting ferroptosis exerts neuroprotection, and this is another neuroprotective mechanism of Ruxo on TBI.
Trypsin-Mediated Sensitization to Ferroptosis Increases the Severity of Pancreatitis in Mice.
Liu Ke,Liu Jiao,Zou Borong,Li Changfeng,Zeh Herbert J,Kang Rui,Kroemer Guido,Huang Jun,Tang Daolin
Cellular and molecular gastroenterology and hepatology
BACKGROUND & AIMS:Pancreatitis is characterized by acinar cell death and persistent inflammation. Ferroptosis is a type of lipid peroxidation-dependent necrosis, which is negatively regulated by glutathione peroxidase 4. We studied how trypsin, a serine protease secreted by pancreatic acinar cells, affects the contribution of ferroptosis to triggering pancreatitis. METHODS:In vitro, the mouse pancreatic acinar cell line 266-6 and mouse primary pancreatic acinar cells were used to investigate the effect of exogenous trypsin on ferroptosis sensitivity. Short hairpin RNAs were designed to silence gene expression, whereas a library of 1080 approved drugs was used to identify new ferroptosis inhibitors in 266-6 cells. In vivo, a Cre/LoxP system was used to generate mice with a pancreas-specific knockout of Gpx4 (Pdx1-Cre;Gpx4 mice). Acute or chronic pancreatitis was induced in these mice (Gpx4 mice served as controls) by cerulein injections or a Lieber-DeCarli alcoholic liquid diet. Pancreatic tissues, acinar cells, and serum were collected and analyzed by histology, immunoblot, quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, or immunohistochemical analyses. RESULTS:Supraphysiological doses of trypsin (500 or 1000 ng/mL) alone did not trigger significant cell death in 266-6 cells and mouse primary pancreatic acinar cells, but did increase the sensitivity of these cells to ferroptosis upon treatment with cerulein, L-arginine, alcohol, erastin, or RSL3. Proteasome 26S subunit, non-adenosine triphosphatase 4-dependent lipid peroxidation caused ferroptosis in pancreatic acinar cells by promoting the proteasomal degradation of glutathione peroxidase 4. The drug screening campaign identified the antipsychotic drug olanzapine as an antioxidant inhibiting ferroptosis in pancreatic acinar cells. Mice lacking pancreatic Gpx4 developed more severe pancreatitis after cerulein infection or ethanol feeding than control mice. Conversely, olanzapine administration protected against pancreatic ferroptotic damage and experimental pancreatitis in Gpx4-deficient mice. CONCLUSIONS:Trypsin-mediated sensitization to ferroptotic damage increases the severity of pancreatitis in mice, and this process can be reversed by olanzapine.
Ferrostatin-1 Alleviates White Matter Injury Via Decreasing Ferroptosis Following Spinal Cord Injury.
Ge Hongfei,Xue Xingsen,Xian Jishu,Yuan Linbo,Wang Long,Zou Yongjie,Zhong Jun,Jiang Zhouyang,Shi Jiantao,Chen Tunan,Su Hong,Feng Hua,Hu Shengli
Spinal cord injury (SCI), a devastating neurological impairment, usually imposes a long-term psychological stress and high socioeconomic burden for the sufferers and their family. Recent researchers have paid arousing attention to white matter injury and the underlying mechanism following SCI. Ferroptosis has been revealed to be associated with diverse diseases including stroke, cancer, and kidney degeneration. Ferrostatin-1, a potent inhibitor of ferroptosis, has been illustrated to curb ferroptosis in neurons, subsequently improving functional recovery after traumatic brain injury (TBI) and SCI. However, the role of ferroptosis in white matter injury and the therapeutic effect of ferrostatin-1 on SCI are still unknown. Here, our results indicated that ferroptosis played a pivotal role in the secondary white matter injury, and ferrostatin-1 could reduce iron and reactive oxygen species (ROS) accumulation and downregulate the ferroptosis-related genes and its products of IREB2 and PTGS2 to further inhibit ferroptosis in oligodendrocyte, finally reducing white matter injury and promoting functional recovery following SCI in rats. Meanwhile, the results demonstrated that ferrostatin-1 held the potential of inhibiting the activation of reactive astrocyte and microglia. Mechanically, the present study deciphers the potential mechanism of white matter damage, which enlarges the therapeutic effects of ferrostatin-1 on SCI and even in other central nervous system (CNS) diseases existing ferroptosis.
Cadmium attenuates testosterone synthesis by promoting ferroptosis and blocking autophagosome-lysosome fusion.
Zeng Ling,Zhou Jinzhao,Wang Xiaofei,Zhang Yanwei,Wang Mei,Su Ping
Free radical biology & medicine
Ferroptosis is a newly defined programmed cell death pathway characterized by iron overload and lipid peroxidation. Increasing studies show that autophagy regulates testosterone synthesis and promotes ferroptosis. Testosterone is essential for sexual development and the maintenance of male characteristics. The deficiency of testosterone induced by cadmium (Cd) can severely affect male fertility. However, the underlying mechanism of testosterone reduction after Cd exposure remains blurry. In this study, we found that Cd affected iron homeostasis and elicited ferroptosis, ultimately reducing testosterone production. Mechanically, our findings revealed that Cd-induced ferroptosis depended upon the excessive activation of Heme oxygenase 1 (HMOX1) and the release of free iron from heme. Additionally, Cd exposure promoted autophagosome formation but blocked autophagosome-lysosome fusion, which attenuated the absorption of total cholesterol and triglycerides, further aggravating testosterone synthesis disorder. Collectively, Cd induced ferroptosis by iron homeostasis dysregulation, mediated by excessive activation of HMOX-1. The disruption of autophagy flow contributed to Cd-induced testicular dysfunction and attenuated testosterone synthesis.
N-methyladenosine modification regulates ferroptosis through autophagy signaling pathway in hepatic stellate cells.
Shen Min,Li Yujia,Wang Yingqian,Shao Jiangjuan,Zhang Feng,Yin Guoping,Chen Anping,Zhang Zili,Zheng Shizhong
Ferroptosis is a recently identified non-apoptotic form of cell death characterized by iron-dependent lipid peroxidation. However, the underlying exact mechanisms remain poorly understood. Here, we report that the total levels of N-methyladenosine (mA) modification are evidently increased upon exposure to ferroptosis-inducing compounds due to the upregulation of methylase METTL4 and the downregulation of demethylase FTO. Interestingly, RNA-seq shows that mA modification appears to trigger autophagy activation by stabilizing BECN1 mRNA, which may be the potential mechanism for mA modification-enhanced HSC ferroptosis. Importantly, YTHDF1 is identified as a key mA reader protein for BECN1 mRNA stability, and knockdown of YTHDF1 could prevent BECN1 plasmid-induced HSC ferroptosis. Noteworthy, YTHDF1 promotes BECN1 mRNA stability and autophagy activation via recognizing the mA binding site within BECN1 coding regions. In mice, erastin treatment alleviates liver fibrosis by inducing HSC ferroptosis. HSC-specific inhibition of mA modification could impair erastin-induced HSC ferroptosis in murine liver fibrosis. Moreover, we retrospectively analyzed the effect of sorafenib on HSC ferroptosis and mA modification in advanced fibrotic patients with hepatocellular carcinoma (HCC) receiving sorafenib monotherapy. Attractively, the mA modification upregulation, autophagy activation, and ferroptosis induction occur in human HSCs. Overall, these findings reveal novel signaling pathways and molecular mechanisms of ferroptosis, and also identify mA modification-dependent ferroptosis as a potential target for the treatment of liver fibrosis.